The biological mechanisms of neoplastic transformation have been shown in this laboratory to result from the development of defects in the integrated control of cell differentiation and proliferation in cultured mesenchymal stem cells. These defects are expressed as the inability to regulate cellular differentiation and/or proliferation at distinct states in the G[unreadable]1[unreadable] phase of the cell cycle. This conclusion has been established by studies on normal cultured stem cells and on 25 cell clones that were selected because they express one or more stable defects in these regulatory mechanisms. It has also been determined that an initiator of carcinogenesis selectively induces differentiation control defects in cultured stem cells and that proliferation control defects develop later in the transformation process. Based on these observations, we have developed a model that suggests that the initiation of carcinogenesis is associated with expression of aberrant differentiation control and that the promotion of carcinogenesis is associated with the expression of aberrant control of cellular proliferation. Our studies are designed to attempt to determine the biochemical and molecular basis for the regulation of cellular differentiation in normal stem cells and for the development of differentiation control defects during carcinogenesis. Our studies are also designed to establish the relevance of these discoveries to human carcinogenesis. (N)